Role of lymphocytes for the progression of a genetically determined cardiomyopathy

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Recent experimental data indicate that both chronic remodeling after myocardial infarction and hypertrophic remodeling in response to pathological afterload are promoted by autoreactive T-cells. Moreover, there are clinical study results pointing to an adaptive immune response, including autoantibodies against myocardial epitopes, in dilative cardiomyopathies. However, the role of lymphocytes for the progression of genetic cardiomyopathies is not well established.Our own data showed myocardial inflammation and autoantibodies against myocardial epitopes in a mouse model of the inherited Duchenne cardiomyopathy (MDX) already at an early stage when there is no obvious myocardial pathology. MDX mice on a genetic background that leads to a broad defect in the adaptive immune system (SCID) show significantly less fibrosis and myocardial hypertrophy then MDX mice on a wildtype background. Therefore, in this project we want to study the role of T- and B-lymphocytes and autoantibodies for the progression of the cardiomyopathy in the MDX mouse model. We project to perform bone marrow reconstitution experiments in MDX-SCID mice to address the role of various lymphocyte subsets. We further hypothesize that the adaptive immune systems shapes the phenotype of myocardial macrophages and thereby promotes disease progression. Therefore, we will perform flow cytometric analyses of the leukocytes in the myocardium. For a broader and more unbiased approach we will phenotype myocardial leukocytes by a novel single cell proteo-transcriptomic approach. This will be accompanied by RNA-sequencing based transcriptome analyses of endothelial cells, fibroblasts, and cardiomyocytes to get deeper insights into the interaction of leukocytes and non-leukocytes within the myocardium.This research project aims to get a deeper understanding of the role of the adaptive immune system for the progression of an inherited cardiomyopathy. We expect that the mechanism identified here apply to other genetic cardiomyopathies and thus the results will help to identify lymphocyte subsets as potential therapeutic targets to decelerate the progression of inherited cardiomyopathies.